The MTHFR C677T variant is associated with responsiveness to disulfiram treatment for cocaine dependency

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Abstract

Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2 weeks and then randomized into disulfiram (250mg/day, N=32)and placebo groups (N=35)for 10weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10 weeks of the study (N= 56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT orTT MTHFR genotype group (N= 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N=24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81-69% (p= 0.007). Conclusion: This study indicates that a patient's MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630. © 2013 Spellicy, Kosten, Hamon, Harding and Nielsen.

Figures

  • FIGURE 1 | Schematic of the folic acid metabolic cycle. Dietary folate (vitamin B12) is converted to dihydrofolate (DHF), and subsequently metabolized to tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). THF is converted to 5,10-methylene THF by methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), then to 5-methyl THF by methylene tetrahydrofolate reductase (MTHFR). 5-methyl THF is demethylated and combined with homocysteine to form methionine by 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Methionine is transformed to S-adenosyl methionine (SAM) by methionine S-adenosyltransferase (MAT). SAM-dependent methyltransferases metabolize SAM into S-adenysyl homocysteine (SAH) methylating downstream targets. SAH is converted to homocysteine by SAH hydrolase.
  • Table 1 | Clinical and demographic characterization by treatment and genotype.
  • FIGURE 2 | Response to disulfiram therapy by treatment group (N = 56). Cocaine-positive urine toxicology screens are shown for each 2 week time period across the 12-week trial as percent positive urines. The placebo treatment group (N =32) is represented by a solid line and the disulfiram (250 mg/day) treatment group (N =24) is represented by a dashed line. Standard error bars are shown for each time point. Only data from study participants with complete urine toxicologies were included in the analysis.
  • FIGURE 3 | Response of MTHFR C677T CC and CT/TT genotype groups to disulfiram pharmacotherapy in individuals with complete urine toxicology data (N = 56). Cocaine-positive urine toxicologies are shown for each 2 week time period across the 12-week trial in percent positive urines. The solid line represents time points for the placebo treatment group and the dashed line represents time points for the disulfiram treatment group (250 mg/day). Top panel: patients with the MTHFR CT/TT or TT genotype (disulfiram, N=14; placebo, N =18). Bottom panel: patients with MTHFR CC genotype (disulfiram, N =10; placebo, N =14). Standard error bars are shown for each time point.

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APA

Spellicy, C. J., Kosten, T. R., Hamon, S. C., Harding, M. J., & Nielsen, D. A. (2013). The MTHFR C677T variant is associated with responsiveness to disulfiram treatment for cocaine dependency. Frontiers in Psychiatry, 3(JAN). https://doi.org/10.3389/fpsyt.2012.00109

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